PDBsum entry 2o3r

Hydrolase

PDB id: 2o3r

Contents

Protein chain

252 a.a. *

Ligands

CXR ×2

Waters ×400

* Residue conservation analysis

PDB id:

2o3r

Name:

Hydrolase

Title:

Structural basis for formation and hydrolysis of calcium messenger cyclic adp-ribose by human cd38

Structure:

Adp-ribosyl cyclase 1. Chain: a, b. Fragment: extracellular domain, residues 45-300. Synonym: cyclic adp-ribose hydrolase 1, cadpr hydrolase 1, lymphocyte differentiation antigen cd38, t10, acute lymphoblastic leukemia cells antigen cd38. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cd38. Expressed in: pichia pastoris. Expression_system_taxid: 4922.

Biol. unit:

Monomer (from PQS)

Resolution:

1.75Å R-factor: 0.185 R-free: 0.229

Authors:

Q.Liu,I.A.Kriksunov,R.Graeff,H.C.Lee,Q.Hao

Key ref:

Q.Liu et al. (2007). Structural basis for formation and hydrolysis of the calcium messenger cyclic ADP-ribose by human CD38. J Biol Chem, 282, 5853-5861. PubMed id: 17182614 DOI: 10.1074/jbc.M609093200

Date:

01-Dec-06 Release date: 12-Dec-06

Protein chains

P28907  (CD38_HUMAN) -  ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 from Homo sapiens

Seq: 300 a.a.

Struc: 252 a.a.*

* PDB and UniProt seqs differ at 6 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: E.C.2.4.99.20 - 2'-phospho-ADP-ribosyl cyclase/2'-phospho-cyclic-ADP-ribose transferase.
• Reaction: nicotinate + NADP⁺ = nicotinate-adenine dinucleotide phosphate + nicotinamide

nicotinate (Bound ligand (Het Group name = CXR) matches with 72.92% similarity) + NADP(+) = nicotinate-adenine dinucleotide phosphate + nicotinamide

• Enzyme class 2: E.C.3.2.2.- - ?????
• Enzyme class 3: E.C.3.2.2.6 - ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase.
• Reaction: NAD⁺ + H2O = ADP-D-ribose + nicotinamide + H⁺

NAD(+) + H2O = ADP-D-ribose (Bound ligand (Het Group name = CXR) matches with 97.22% similarity) + nicotinamide + H(+)

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1074/jbc.M609093200

J Biol Chem 282:5853-5861 (2007)

PubMed id: 17182614

Structural basis for formation and hydrolysis of the calcium messenger cyclic ADP-ribose by human CD38.

Q.Liu, I.A.Kriksunov, R.Graeff, H.C.Lee, Q.Hao.

ABSTRACT

Human CD38 is a multifunctional ectoenzyme responsible for catalyzing the conversions from nicotinamide adenine dinucleotide (NAD) to cyclic ADP-ribose (cADPR) and from cADPR to ADP-ribose (ADPR). Both cADPR and ADPR are calcium messengers that can mobilize intracellular stores and activate influx as well. In this study, we determined three crystal structures of the human CD38 enzymatic domain complexed with cADPR at 1.5-A resolution, with its analog, cyclic GDP-ribose (cGDPR) (1.68 A) and with NGD (2.1 A) a substrate analog of NAD. The results indicate that the binding of cADPR or cGDPR to the active site induces structural rearrangements in the dipeptide Glu(146)-Asp(147) by as much as 2.7 A) providing the first direct evidence of a conformational change at the active site during catalysis. In addition, Glu(226) is shown to be critical not only in catalysis but also in positioning of cADPR at the catalytic site through strong hydrogen bonding interactions. Structural details obtained from these complexes provide a step-by-step description of the catalytic processes in the synthesis and hydrolysis of cADPR.

Selected figure(s)

Figure 1.
FIGURE 1. Structural overview of shCD38 complexed with various substrates and products. The structure of shCD38 is shown as gray transparent surface. Cyclic ADPR (A), cGDPR (B), and NGD (C) are drawn as sticks and colored with the scheme: C, white;N, blue;O, red;P, orange. Figures were prepared with Pymol.

Figure 5.
FIGURE 5. cADPR recognition and catalysis. A, stereo model of the cADPR complex with the bound cADPR transformed to the catalytic position seen in the cGDPR complex. The positions of the protein residues were unchanged and only cADPR was modeled. The bound cGDPR is shown as yellow sticks as reference. The adenine ring on cADPR and guanine ring on cGDPR are coplanar and parallel to the ring of Trp^189. Residue Glu^146 in the position that it adopts in the cADPR complex (Fig. 2) is shown as magenta sticks; two dashed blue lines and associated values indicate the distances between adenine and Glu^146. B, model showing the dynamics of Glu^146 during cADPR catalysis. Glu^146 is shown in green when it is in the position as seen in the apo E226Q structure, while it is colored yellow when it is in the position as seen in the cGDPR-E226Q complex. The active site and its nearest surface to Glu^146 are shown as gray surface. Asp^147 as seen in the cGDPR-E226Q structure is located on the surface of CD38 and colored magenta. Red and dark arrows show the reciprocal movement of Glu^146 and Asp^147 during the cADPR binding and release, respectively. The conformational changes of Glu^146-Asp^147 are crucial in regulating cADPR catalysis.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 5853-5861) copyright 2007.

Figures were selected by an automated process.